Primary biliary cholangitis (PBC) is a rare chronic cholestatic disease that despite current therapy has significant ongoing unmet needs, including risks of cirrhosis and life-impairing symptoms. The current treatment approach is a step-up model, wherein first-line therapy, ursodeoxycholic acid (UDCA), is given for a minimum of 12 months before the addition of second-line therapy is considered for non-responding patients. This ‘waiting to fail’ approach, focused on the needs of low-risk patients, allows, we postulate, a key process of biliary epithelial cell (BEC) senescence to become established, driving accelerated bile duct loss and aggressive disease. Preclinical mouse modelling has shown that early use of the farnesoid X receptor agonist obeticholic acid (OCA), currently only used as second-line therapy following UDCA failure, reverses BEC senescence, changing the clinical course of disease. Here, we describe the design of the Optimising Primary thErapy in pRimAry biliary cholangitis (OPERA) trial. The aim of OPERA is to explore a new paradigm for disease-modifying treatment of PBC: risk-informed early treatment stratification, with patients at increased risk offered UDCA and OCA combination with the goal of complete biochemical remission.

OPERA is a multicentre, randomised, double-blind, placebo-controlled trial of OCA in combination with UDCA, as first-line treatment for high-risk PBC. This is a multicentre trial in England, which will be undertaken in specialist clinics in secondary/tertiary referral centres (or as per local set up). These centres will be specialists in the area of PBC management and will manage patients from across their local region. OPERA will recruit and randomise 106 adults, within 6 months of PBC diagnosis, who are at an enhanced risk of non-response to standard first-line therapy, between either: (1) UDCA and OCA or (2) UDCA and matched placebo in a 1:1 ratio. The primary efficacy outcome measure is the percentage of participants showing normalisation of serum alkaline phosphatase and total bilirubin values at 26 weeks (disease remission).

Favourable ethical opinion was received from London – Riverside Research Ethics Committee (reference: 22/LO/0878). Potential participants will be fully informed of their rights and the benefits and harms of the trial by the research team before giving informed consent to participate in the trial. Results will be disseminated in peer-reviewed publications, at national and international conferences, in peer-reviewed journals and to participants and the public (using lay language).

ISRCTN17176388.

Heart failure (HF) remains a major global health challenge, particularly in low-resource settings where access to comprehensive cardiac rehabilitation (CR) is limited. Yoga, a culturally contextualised mind-body intervention, holds promise as an adjunctive therapy in CR. The Yoga-EndOmics study aims to evaluate the effects of Yoga-based cardiac rehabilitation (Yoga-CaRe) on gene expression, endothelial function, vascular biomarkers and clinical outcomes in systolic HF, providing mechanistic insights into its potential integration into conventional cardiac rehabilitation.

This is a prospective, randomised, open-label, blinded-endpoint (PROBE) mechanistic trial enrolling 78 patients with HF with reduced ejection fraction (HFrEF). Participants will be randomised in a 1:1 ratio to receive either a structured Yoga-CaRe intervention or enhanced standard care for 3 months. The Yoga-CaRe group will attend 20 supervised sessions with guided home practice involving tailored asanas, pranayama and meditation. Primary outcomes are changes in endothelial-dependent flow-mediated dilation (FMD) and functional exercise capacity at 3 months. Secondary outcomes include changes in arterial compliance and stiffness, circulating biomarkers of endothelial dysfunction, oxidative stress and inflammation, and immediate changes in global gene expression profiles in peripheral blood mononuclear cells following the Yoga-CaRe intervention. Data will be analysed using analysis of covariance (ANCOVA) for between-group comparisons and significant analysis of microarray (SAM) for global gene expression profiles.

The study has received ethical clearance from the Institutional Ethics Committee of the SDM College of Medical Sciences and Hospital, India (SDMIEC/2025/1072) and is registered with the Clinical Trials Registry of India. Findings will be disseminated through peer-reviewed journals, scientific conferences and stakeholder engagement platforms to inform future integrative strategies in HF management.

CTRI/2023/12/060758